Skin Cancer xxix, 2011 : Page 52

HEALTH Non-Surgical Treatment of Skin Cancers And Precancers MEGAN NICOLE MOODY, MD, MPH, JENNIFER MICHELLE LANDAU, BS, ATON HOLZER, MD, AND LEONARD H. GOLDBERG, MD M ost often, surgery is the single best treatment for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the two most common types of non-melanoma skin cancer (NMSC). However, other treatments are also effective for NMSC as well as actinic keratosis (AKs), the most common skin precancer. In certain situations, non-surgical alternatives such as cryotherapy, radiotherapy, and topical medications may be preferable — for example, in patients with bleeding problems, cardiac issues, poor wound heal-ing, or other conditions that leave them at high risk for postoperative complications. is cheap, environmentally friendly, readily available, and can be used in an outpatient setting. A local anesthetic may be used prior to cryotherapy when treating cancers and AKs, because cryotherapy is associated with a modest amount of pain. Most options can be used to treat skin cancer patients who choose not to have surgery, or are poor surgical candidates for health reasons, or for whom surgery will not be effective. These side effects, com bi ned w it h radiation’s high cost and inability to provide margin control (precision in identifying and removing residual tumor extensions at the margins of the tumor), have caused radiation to fall out of favor as a skin cancer treatment. Radiation is most commonly reserved for patients who are poor surgical candidates or do not desire surgery, as well as for palliation of inoperable tumors. 5-FLUOROURACIL (EFUDEX ® , CARAC ® , ADRUCIL ® AND FLUOROPLEX ® ) CRYOTHERAPY (CRYOSURGERY) Cryotherapy has been used to treat AKs and early-stage skin cancers for decades. It involves topical application of liquid nitrogen (LN 2 ) to visible skin lesions via spray or cotton-tipped ap-plicator. LN 2 freezes the lesions, which subsequently fall off. Recently, an infrared sensor with a color-coded light system was incorporated. The sensor indicates when the desired “cell kill” temperature (-5° C) is reached, decreasing the likelihood of both under-treatment and exces-sive tissue injury. 1 Liquid nitrogen 52 RADIOTHERAPY Radiation therapy (radiotherapy) was ﬁrst used to treat skin cancers in the early 1900s. X-ray beams are directed at the tumor, leading to cell death and eventual destruction of the cancer. Though it can selectively destroy tumor cells while limiting damage to adjacent tissue, radiotherapy re-quires multiple visits over weeks and has numerous potential side effects. The topical medication 5-ﬂuorouracil (5-FU) is approved by the US Food and Drug Administration (FDA) for the treatment of AKs and superﬁcial (non-invasive) BCCs. 5-FU liquid or ointment halts uncontrolled cell growth and induces cell death. It is especially active in cells with high rates of replication, making it rela-tively selective for cancer cells. The side effects associated with 5-FU treatment (such as extreme temporary reddening and stinging sensations as well as sun sensitivity) can be signiﬁ-cant and decrease patient compliance with treatment protocols.Recurrence rates are high for both AK and BCC. S K I N CA N C E R F O UND A T I O N J O URN A L

Non-Surgical Treatment Of Skin Cancers And Precancers

Most often, surgery is the single best treatment for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the two most common types of non-melanoma skin cancer (NMSC). However, other treatments are also effective for NMSC as well as actinic keratosis (AKs), the most common skin precancer. In certain situations, non-surgical alternatives such as cryotherapy, radiotherapy, and topical medications may be preferable – for example, in patients with bleeding problems, cardiac issues, poor wound healing, or other conditions that leave them at high risk for postoperative complications.

CRYOTHERAPY (CRYOSURGERY)
Cryotherapy has been used to treat AKs and early-stage skin cancers for decades. It involves topical application of liquid nitrogen (LN2) to visible skin lesions via spray or cotton-tipped applicator. LN2 freezes the lesions, which subsequently fall off. Recently, an infrared sensor with a color-coded light system was incorporated. The sensor indicates when the desired "cell kill" temperature (-5° C) is reached, decreasing the likelihood of both under-treatment and excessive tissue injury.1 Liquid nitrogen is cheap, environmentally friendly, readily available, and can be used in an outpatient setting. A local anesthetic may be used prior to cryotherapy when treating cancers and AKs, because cryotherapy is associated with a modest amount of pain.

RADIOTHERAPY
Radiation therapy (radiotherapy) was first used to treat skin cancers in the early 1900s. X-ray beams are directed at the tumor, leading to cell death and eventual destruction of the cancer. Though it can selectively destroy tumor cells while limiting damage to adjacent tissue, radiotherapy requires multiple visits over weeks and has numerous potential side effects. These side effects, combined with radiation's high cost and inability to provide margin control (precision in identifying and removing residual tumor extensions at the margins of the tumor), have caused radiation to fall out of favor as a skin cancer treatment. Radiation is most commonly reserved for patients who are poor surgical candidates or do not desire surgery, as well as for palliation of inoperable tumors.

5-FLUOROURACIL (EFUDEX®, CARAC®, ADRUCIL® AND FLUOROPLEX®)
The topical medication 5-fluorouracil (5-FU) is approved by the US Food and Drug Administration (FDA) for the treatment of AKs and superficial (non-invasive) BCCs. 5-FU liquid or ointment halts uncontrolled cell growth and induces cell death. It is especially active in cells with high rates of replication, making it relatively selective for cancer cells. The side effects associated with 5-FU treatment (such as extreme temporary reddening and stinging sensations as well as sun sensitivity) can be significant and decrease patient compliance with treatment protocols. Recurrence rates are high for both AK and BCC.

IMIQUIMOD (ALDARATM, ZYCLARA®)
When applied to AKs and superficial BCCs, imiquimod cream (5 percent or 3.75 percent) enhances the activity of interferon and other immune cells that destroy cancer and virus-infected cells. Like 5-FU, imiquimod can cause adverse effects and sun sensitivity and thus difficulty with patient compliance. There is also a risk of recurrence due to incomplete destruction of the tumor. The 5 percent solution is FD Aapproved for both AK and superficial BCC, and the 3.75 percent cream was recently FDA-approved to treat AKs. Initial reports show effectiveness similar to that of the 5 percent preparation.

PHOTODYNAMIC THERAPY (PDT)
Photodynamic therapy (PDT) can be a good strategy for widespread AKs and multiple superficial NMSCs. It is one of the most promising options for "field therapy," the treatment of an entire severely sun-damaged body area, in an effort to clear up both clinically evident and potentially subclinical, invisible lesions. Studies show that PDT with photosensitizing (light-sensitizing) agents like 5-aminolevulinic acid (ALA) or methyl aminolevulinate (MAL) effectively treats existing AKs, prevents new ones from forming, and inhibits progression of AKs to invasive cancers.2

A topical formulation of ALA or MAL is applied to the treatment area(s) and allowed to develop for 1-3 hours or overnight, during which time the drugs are taken up by precancerous and cancerous cells. A blue or red light is then shone on the treatment area(s), activating the medication and ultimately destroying cancerous and precancerous cells.2

After the procedure, patients must strictly avoid sunlight for at least 48 hours, as subsequent UV exposure will further activate the medication, causing severe sunburns.

LASER THERAPY
Lasers employ specific light wavelengths to treat an array of skin problems, including skin cancers. Ablative lasers vaporize the skin's top layer to destroy lesions; they have been used with varying degrees of success to destroy AKs and superficial NMSCs. However, recurrences are common.

Non-ablative lasers penetrate the skin without removing the top layer. The FDA recently approved a fractionated non-ablative laser (1550-nm erbium doped fiber laser) for AK,3 while another non-ablative laser (pulsed-dye laser) has been shown in some cases to treat small BCCs successfully.4

CAPECITABINE (XELODA)
Capecitabine is a chemotherapeutic agent that, when taken orally, is converted to 5-fluorouracil inside tumor cells. It can be used for both the treatment5 and prevention of skin cancers, particularly in advanced SCC or in SCC-prone solid organ transplant recipients,6 who tend to have high skin cancer rates.7 To date, Capacetabine is FDA-approved only for metastatic colon, breast, and rectal cancers. Initial studies with skin cancer have had promising results; however, the studies are small,5,6 so the risk/benefit ratio is undetermined. Capecitabine is being combined with subcutaneous interferon alpha, an immunotherapy, in some clinical trials.

GDC-0449
GDC-0449 is a small molecule derived from cyclopamine, a chemical naturally produced by the corn lily that inhibits the body's "hedgehog genetic pathway." The hedgehog gene (Hh) is a signaling mechanism made up of proteins that carry developmental information to cells. Improperly functioning Hh pathways that overproduce the proteins have been implicated in the development of BCC and other skin cancers.8 When taken orally, GDC-0449 stops the abnormal activity of Hh and prevents BCCs from growing in otherwise healthy patients as well as those with basal cell nevus syndrome (who are highly prone to developing multiple BCCs).9,10 This medication is not yet FDA-approved, but may prove revolutionary in BCC treatment.

COMPARING NON-SURGICAL AND URGICAL SKIN CANCER TREATMENTS
The majority of these options can be used to treat skin cancer patients who choose not to have surgery, are poor surgical candidates for health reasons, or for whom surgery will not be effective. However, they can be quite expensive. If a patient is a suitable candidate for surgery, it would be hard to justify prolonged use of an irritating and less effective topical medication. When determining the preferred treatment, both patient and physician should take into consideration the type of tumor, the effectiveness of the treatment options, the risks of scarring and other side effects, the convenience or inconvenience of the techniques, the cost of treatment, and the physician's experience in that treatment.

DR. GOLDBERG, a fellow of the Royal College of Physicians, is a leader in Mohs micrographic surgery and the author of more than 250 publications on the subject. He was Chief of Dermatologic Surgery at Baylor College of Medicine, Houston, and is a Fellowship Director for the American College of Mohs Surgery and a past President of the Houston Dermatological Society. Dr. Goldberg is a staff member of The Methodist Hospital, in Houston.

DR. MOODY is currently a clinical research fellow for Dr. Goldberg. She received her medical degree with honors from UT Houston Medical School and will begin her Dermatology Residency at UTMB in July 2011.

MS. LANDAU is currently a clinical research coordinator for Dr. Goldberg. She received her Bachelor's in Science with honors from Yale University and will begin medical school in the fall of 2011.

DR. HOLZER is a fellow in Procedural Dermatology at The Methodist Hospital, Houston. He received his MD with honors in research from the Weill Medical College of Cornell University and completed a dermatology residency at University of Alabama at Birmingham.